Multiple sclerosis (MS) is a chronic, debilitating disease of the central nervous system (CNS) with either relapsing-remitting (RR) or progressive course leading to neurologic deterioration and disability. At time of initial diagnosis, RRMS is the most common form of the disease (Noseworthy, 2000) which is characterized by unpredictable acute episodes of neurological dysfunction (relapses), followed by variable recovery and periods of clinical stability. The vast majority of RRMS patients eventually develop secondary progressive (SP) disease with or without superimposed relapses. Around 15% of patients develop a sustained deterioration of their neurological function from the beginning; this form is called primary progressive (PP) MS. Patients who have experienced a single clinical event (Clinically Isolated Syndrome or “CIS”) and who show lesion dissemination on subsequent magnetic resonance imaging (MRI) scans according to McDonald's criteria, are also considered as having relapsing MS (EMEA Guideline, 2006).
Evidence is accumulating from pathophysiology, pathology, clinical and MRI studies that axonal damage and associated inflammation is characteristic of MS and may occur early in the disease course. It is believed that a confluence of elements must be present for MS to occur: genetic predisposition, immune dysregulation and one or more environmental factors. Although prevalence varies considerably around the world, MS is the most common cause of chronic neurological disability in young adults (Bjartmar, 2002; Fleming, 2002). Anderson et al. estimated that there were about 350,000 physician-diagnosed patients with MS in the United States in 1990 (approx. 140 per 100,000 population) (Anderson, 1992). It is estimated that about 2.5 million individuals are affected worldwide (Compston, 2006). In general, there has been a trend toward an increasing prevalence and incidence of MS worldwide, but the reasons for this trend are not fully understood (Anderson, 1992).
Current therapeutic approaches consist of i) symptomatic treatment ii) treatment of acute relapses with corticosteroids and iii) treatment aimed to modify the course of the disease. Currently approved therapies target the inflammatory processes of the disease. Most of them are considered to act as immunomodulators but their mechanisms of action have not been completely elucidated. Immunosuppressants or cytotoxic agents are also used in some patients after failure of conventional therapies.
Glatiramer Acetate Injection
Glatiramer acetate (GA) is the active substance in Copaxone®, a marketed product indicated for reduction of the frequency of relapses in patients with RRMS. Glatiramer acetate consists of the acetate salts of synthetic polypeptides containing four naturally occurring amino acids: L-glutamic acid, L-alanine, L-tyrosine and L-lysine. The average molecular weight of glatiramer acetate is between 5,000 and 9,000 Daltons. The marketed medicinal product, Copaxone®, contains 20 mg glatiramer acetate and 40 mg mannitol in 1.0 ml water for injection.
Although extensively researched, the mechanism of action of GA in humans remains uncertain and has been the subject of several recent reviews (Arnon, 2007; Ruggiere, 2007; Weber, 2007; Ziemssen, 2007). Based on the preclinical and clinical pharmacology data accumulated in the last four decades of research, it appears that GA's mechanism of action addresses the main pathological mechanisms driving MS, i.e. anti-inflammation, remyelination and neuroprotection (prevention of axonal loss) (Dhib-Jalbut, 2003).
The currently available data suggest that after subcutaneous (sc) injection, GA binds HLA class II (DR) on antigen-presenting cells in lymph nodes. As a result, GA can block the activation of myelin-reactive T cells or render these cells anergic. In addition, GA induces GA-specific Th2 cells that cross the blood-brain barrier (BBB) and produce bystander suppression as a result of cross-recognition of myelin antigens. These cells secrete both anti-inflammatory cytokines as well as neurotrophic factors and therefore induce both anti-inflammatory and neuroprotective functions (Dhib-Jalbut, 2002).
Clinical experience with GA consists of information obtained from completed and ongoing clinical trials and from post-marketing experience. The clinical program includes three double-blind, placebo-controlled studies in RRMS subjects treated with GA 20 mg/day (Bornstein, 1987; Comi, 2001; Johnson, 1998). A significant reduction in the number of relapses, compared with placebo, was seen. In the largest controlled study, the relapse rate was reduced by 32% from 1.98 under placebo to 1.34 under GA 20 mg. GA 20 mg has also demonstrated beneficial effects over placebo on MRI parameters relevant to RRMS. A significant effect in median cumulative number of Gd-enhancing lesions over 9 months of treatment (11 lesions in the 20 mg group compared to 17 lesions under placebo) was demonstrated.
The clinical program with GA also includes one double-blind study in chronic-progressive MS subjects (Bornstein, 1991), one double-blind placebo-controlled study in primary progressive patients (Wolinsky, 2007), one double-blind placebo-controlled study in CIS patients (Comi, 2008; Stark, 2009) and numerous open-label and compassionate use studies, mostly in RRMS. The clinical use of GA has been extensively reviewed and published in the current literature (Tselis, 2007; Wolinsky, 2006; Comi, 2008; Comi, 2008).
Safety data accumulated for GA in clinical trials shows that the drug product is safe and well tolerated. However, a reaction termed Immediate Post-Injection Reaction (IPIR) consisting of one or more of the following symptoms: vasodilatation, chest pain, dyspnoea, palpitations or tachycardia was reported for 31% of the GA patients vs. 13% on placebo. Additional adverse reactions reported by patients treated with GA 20 mg with at least 2% higher incidence than with placebo were pain, nausea, anxiety, rash, back pain, chills, face edema, local reaction, lymphadenopathy, vomiting, weight increase, tremor, skin disorder, eye disorder, vaginal candidiasis and injection site atrophy.
In all clinical trials, injection-site reactions were seen to be the most frequent adverse reactions and were reported by the majority of patients receiving GA. In controlled studies, the proportion of patients reporting these reactions, at least once, was higher following treatment with GA (70%) than placebo injections (37%). The most commonly reported injection-site reactions, which were more frequently reported in GA vs. placebo-treated patients, were erythema, pain, mass, pruritus, edema, inflammation and hypersensitivity.
Reducing the number and/or severity of the injection-site reactions in order to promote compliance and improving the quality of life for the patient remains a problem with GA treatment. However, for a drug product composed of peptides and whose mechanism of action is not understood, the effects of any modification cannot be readily predicted. Modifications of the formulation may unpredictably affect efficacy. To accommodate an indicated dose requirement in a limited injection volume, a polypeptide drug needs to be delivered at high concentrations. This alone is a significant problem when dealing with peptides of low solubility such as glatiramer acetate which is described as “sparingly soluble” (Product Monograph, 2009). Furthermore, concentrated polypeptide solutions are prone to additional problems. Such formulations suffer from poor shelf-life, unacceptable turbidity, changes in pH, chemical degradation including hydrolysis and aggregation (both reversible and irreversible) and increases in viscosity; all of which potentially reduce shelf-life and bioavailability (Shire, 2004).
Drug administration by subcutaneous injection results in delivery of the drug to the interstitial area underneath the skin. The fluid environment of the interstitial space is essentially that of plasma although the constituent proteins are at a lower concentration. This physiological medium may conflict with the solubility characteristics of the concentrated peptide drug (Kansara, 2009). Following injection, the interaction of the delivered drug with the interstitial environment dictates the pattern of absorption of the peptide. Formulation characteristics particularly concentration, injection volume and pH, influence the rate of diffusion and absorption by the patient. Because the interstitium also comprises a fibrous matrix of collagen and glycosaminoglycans, it acts as a barrier to the diffusion and permeability of the drug. As a result, drugs delivered in a concentrated form to the interstitial space may be susceptible to enzymatic degradation at the injection site, precipitation and/or aggregation in the interstitial fluid, and endocytic/phagocytic mechanisms (Kansara, 2009). For a peptide drug product such as glatiramer acetate, clinical testing is therefore required to determine whether any modification can effectively reduce the number and severity of injection-site reactions while still substantially maintaining therapeutic efficacy.